In response to microbial infection, innate immune cells (such as macrophages, monocytes, and neutrophils) constitute a front line of defense by ingesting and killing invading pathogens. If the invading pathogens are efficiently eliminated, the inflammatory response resolves normally to restore immunologic homeostasis. In contrast, inefficient pathogen clearance can lead to a rigorous inflammatory response manifested by excessive production of various proinflammatory mediators. Sepsis refers to a systemic inflammatory response syndrome resulting from a microbial infection. As a continuum of increasing clinical severity, “severe sepsis” is defined as sepsis associated with one or more acute organ dysfunctions [1
]. Despite recent advances in antibiotic therapy and intensive care, sepsis is still the most common cause of death in the intensive care units, claiming approximately 225,000 victims annually in the U.S. alone.
The high mortality of sepsis is partly mediated by bacterial endotoxins (e.g., Lipopolysaccharide, LPS) [2
], which activate macrophages and monocytes to release various proinflammatory mediators such as nitric oxide [3
], tumor necrosis factor (TNF) [4
], interleukin (IL)- 1 [5
], interferon (IFN)-γ 6
], and macrophage migration inhibitory factor (MIF) [7
]. These proinflammatory mediators, individually or in combination, contribute to the pathogenesis of lethal systemic inflammation. For instance, neutralizing antibodies to TNF, the first cytokine elaborated in inflammatory cascade, reduces lethality in an animal model of endotoxemic/bacteremic shock [4
]. However, the early kinetics of TNF production makes it difficult to target in a clinical setting [4
], forcing us to search for other late proinflammatory mediators that may offer a wider therapeutic window for the treatment of lethal systemic inflammatory diseases.
Several years ago, we made the seminal observation that a ubiquitous protein, high mobility group box 1 (HMGB1), was released by activated macrophages/monocytes [8
], and functioned as a late mediator of lethal endotoxemia [8
] and sepsis [11
]. Subsequently, we found that aqueous extracts and/or components of three Chinese herbs, Danggui (Angelica sinensis) [14
], Danshen Salvia miltiorrhiza) [15
] and Green tea (Camellia sinensis) [16
] effectively inhibited bacterial endotoxin-induced HMGB1 release in vitro, and protected mice against lethal endotoxemia and sepsis (induced by CLP) in vivo. Here we review accumulating evidence that support a critical role for extracellular HMGB1 as a late mediator of lethal sepsis, and emerging data that suggest several Chinese medicinal herbs as potential theerapeutic agents for experimental sepsis.